Meta!astatic melanoma is a deadly cancer, lacking an effective therapeutic strategy. It is widely acce:ted that dysfunctions of normal homeostatic regulation of melanoblasts result in neoplastic convirsion to melanomas, while the exact molecular mechanism underlying melanoma conversion remains largely unclear. We have recently demonstrated the indispensable role of Notch signaling in the promotion of melanoblast survival. In this proposal, we aim to further translate our understanding of pro-survival role of Notch signaling into melanoma tumorigenesis. We have identified the Bnip3 gene as a novel target of Notch signaling in melanoblasts. Bnip3 is a member of the 5H3-only proapopl: otic proteins and has been implicated in the hypoxia-Induced autophagic cell death. Hypoxia adapl:atlon is thought to be critical for metastatic progression of melanoma. Therefore, we hypothesize that NOTCH signaling plays an improtant role in protecting melanoma cells from hypo:da-induced autophagic cell death, which confers hypoxia adaptation to melanoma cells and promotes melanoma metastatic spread. In this proposal, we will integrate biochemical and genetic approaches both in vitm and in vivo (i) to delineate the function of Notch signaling in the promution of melanoma survival against hypoxia-induced cell death;(ii) to define the role of Bnip3, as a novel target of Notch signaling, in the regulation of melanoblast cell death;(iii) to elucidate the functi:n of Notch signaling in promoting metastatic speread of melanoma. Our proposal will uncover a novel role of Notch signaling in promoting melanoblast survival and metastatic potential of malignant melanoma, and provide new insights into development of a novel therapeutic strategie for melanoma.